Showing papers by "John Radcliffe Hospital published in 1996"

Life with 6000 Genes

Abstract: The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration. The sequence of 12,068 kilobases defines 5885 potential protein-encoding genes, approximately 140 genes specifying ribosomal RNA, 40 genes for small nuclear RNA molecules, and 275 transfer RNA genes. In addition, the complete sequence provides information about the higher order organization of yeast's 16 chromosomes and allows some insight into their evolutionary history. The genome shows a considerable amount of apparent genetic redundancy, and one of the major problems to be tackled during the next stage of the yeast genome project is to elucidate the biological functions of all of these genes.

Phenotypic Analysis of Antigen-Specific T Lymphocytes

Abstract: Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.

A genome-wide search for quantitative trait loci underlying asthma

Abstract: ASTHMA now affects one child in seven in the United Kingdom1. Most cases (95%) of childhood asthma are associated with atopy, the immunoglobulin E (IgE)-mediated familial syndrome of allergic asthma, eczema and rhinitis. Segregation analysis has consistently suggested the presence of major genes influencing atopy and IgE levels2–4, with the expectation that these genes may be identified by positional cloning or the examination of candidate genes. Here we report the results of a genome-wide search for linkage to one qualitative and four quantitative traits associated with allergic (atopic) asthma. We have identified six potential linkages (P < 0.001), five of which are to quantitative traits. Monte Carlo simulations show that 1.6 false-positive linkages at this level of significance would be expected from the data. One linkage, to chromosome Ilql3, has been established previously5. Three of the new loci show evidence of linkage to a second panel of families, in which maternal effects and pleiotropy of linked phenotypes are seen. The results demonstrate the extent and the complexity of the genetic predisposition to asthma.

Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

Predicting outcome in severe ulcerative colitis.

Abstract: BACKGROUND: Simple criteria are needed to predict which patients with severe ulcerative colitis will respond poorly to intensive medical treatment and require colectomy. AIMS: To find out if the early pattern of change in inflammatory markers or other variables could predict the need for surgery and to evaluate the outcome of medical treatment during one year follow up. PATIENTS: 51 consecutive episodes of severe colitis (Truelove and Witts criteria) affecting 49 patients admitted to John Radcliffe Hospital, Oxford. METHODS: Prospective study monitoring 36 clinical, laboratory, and radiographic variables. All episodes treated with intravenous and rectal hydrocortisone and 14 of 51 with cyclosporine. RESULTS: Complete response in 21 episodes ( 3 stools or visible blood on day 7, but no colectomy), and colectomy on that admission in 15. During the first five days, stool frequency and C reactive protein (CRP) distinguished between outcomes (p 45 mg/l, would require colectomy. For patients given cyclosporine, four of 14 avoided colectomy but two continued to have symptoms. After admission, complete responders remained in remission for a median nine months and had a 5% chance of colectomy. Incomplete responders had a 60% chance of continuous symptoms and 40% chance of colectomy. CONCLUSIONS: After three days intensive treatment, patients with frequent stools (> 8/day), or raised CRP (> 45 mg/l) need to be identified, as most will require colectomy on that admission. The role of cyclosporine for treating severe colitis has yet to be defined. After seven days' treatment, patients with > 3 stools/day of visible blood have a 60% chance of continuous symptoms and 40% chance of colectomy in the following months.

A DEAD-box RNA helicase in the Escherichia coli RNA degradosome

Abstract: THE Escherichia coli RNA degradosome is a multi-enzyme complex that contains the exoribonuclease polynucleotide phosphorylase (PNPase) and the endoribonuclease RNase E1,2. Both enzymes are important in RNA processing and messenger RNA degradation3–14. Here we report that enolase and RhlB are two other major components of the degradosome. Enolase is a glycolytic enzyme with an unknown role in RNA metabolism. RhlB is a member of the DEAD-box family of ATP-dependent RNA helicases, which are found in both prokaryotes and eukaryotes15–26. We show that the degradosome has an ATP-dependent activity that aids the degradation of structured RNA by PNPase. Incubation of the degradosome with affinity-purified antibody against RhlB inhibited the ATP-stimulated RNA degradation. These results suggest that RhlB acts by unwinding RNA structures that impede the processive activity of PNPase. RhlB is thus an important enzyme in mRNA turnover.

Large clonal expansions of CD8 + T cells in acute infectious mononucleosis

Abstract: Primary infection with Epstein–Barr virus often results in the clinical syndrome of acute infectious mononucleosis (glandular fever). This illness is characterized by a striking lymphocytosis, the nature of which has been controversial. We show that large monoclonal or oligoclonal populations of CD8+ T cells account for a significant proportion of the lymphocytosis and provide molecular evidence that these populations have been driven by antigen. The results suggest that the selective and massive expansion of a few dominant clones of CD8+ T cells is an important feature of the primary response to this virus.

Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK.

Abstract: 'To whom correspondence should be addressed We investigated the length of time between the onset of pain symptoms and the surgical diagnosis of endometriosis hi women from the UK and the USA. A total of 218 women with surgically confirmed disease, recruited through endometriosis self-help groups, completed a postal questionnaire. The mean ± SD delay hi diagnosis for women from the USA was 11.73 ± 9.05 years, significantly higher than the equivalent delay of 7.96 ± 7.92 years for women from the UK (P < 0.01). The stage of disease did not affect the length of time between the onset of symptoms and diagnosis. Therefore there is considerable delay hi the diagnosis of endometriosis for women from both the UK and the USA. Efforts to reduce this delay are required to minimize the suffering of women with this disease.

New insights into the mobilization and phagocytic activity of dendritic cells.

Abstract: A study published in this issue of The Journal of Experimental Medicine, sheds new light on the behavior and functions of dendritic cells (DC) which play a pivotal role in initiation of T and T-dependent immune responses (1). The study is important in at least three respects: first, it provides information on recruitment of DC progenitors to a non-lymphoid tissue, the liver; second, it provides evidence that DC have transient phagocytic activity for particulates in vivo, a prerequisite for induction of immune responses against bacteria for example; and third, it defines a migration pathway for DC, that have acquired particulates from the blood, from the liver to draining nodes. To put this paper (1) into context it is necessary to summarize the general consensus of understanding about the DC lineage that has emerged over the past decade or so. DC progenitors that originate from the bone marrow of adult mammals enter the blood and seed non-lymphoid tissues, where they develop into a stage of DC (sometimes referred to as immature DC) with optimal capabilities for antigen uptake and processing, MHC production, and the formation of foreign peptide-MHC complexes (\"processing\" DC). These cells are localized in epitheha, such as skin epidermis, gut, genito-urinary tract, and the lung and airways, and in the interstitial spaces of many solid organs such as heart and kidney. Inflammatory mediators (cytokines and other agents) then promote their maturation and migration out of non-lymphoid tissues into blood and/or afferent lymph. These migratory cells enter secondary lymphoid tissues where they express newly acquired capabilities for the initiation of primary T and T-dependent immune responses, at least in part due to their expression of costimulatory molecules and synthesis of certain cytokines such as IL-12 (\"presenting\" DC, sometimes referred to as mature DC). Migratory DC, travelling between non-lymphoid and secondary lymphoid tissues, are generally considered to be undergoing \"maturation\" from the processing to presenting stages, although maturation is likely to be initiated within non-lymphoid tissues and to continue within secondary lymphoid tissues. At the outset, it is therefore convenient to define four stages of the DC lineage in distinct anatomical compartments: DC progenitors in bone marrow and blood; immature DC at the processing stage in peripheral non-lymphoid organs; migratory DC in the process of maturation in afferent lymph and blood; and mature DC at the presenting stage in secondary lymphoid tissues (2-4). Arguably this view is an over-simplification. For example, DC progenitors may enter secondary lymphoid tissues directly; some DC in non-lymphoid tissues may possess a degree of costimulatory activity; some DC in lymphoid tissues may be capable of antigen uptake and processing to some extent; and DC in thymus may play a role in the induction of T cell tolerance to self peptide-MHC complexes. Nevertheless, it provides a useful framework for understanding how, where, and when DC regulate the induction of primary immune responses. It is also important to add that once antigen-specific T cells have been activated by DC, the activated T cells appear not to require the specialized costimulatory signals that are delivered by DC, and may respond to other types of antigen-presenting cell expressing the peptide-MHC complexes for which they are specific (2, 3). DCProgenitors. A major advance over the past few years has been the ability to grow DC from bone marrow and blood progenitors and to control production of different stages of the lineage in vitro. For example, development of immature human DC is promoted by culture of bone marrow or blood progenitors in the presence of GMCSF and IL-4 (5, 6), and further maturation can be induced by subsequent exposure to TNF-ot or CD40 ligand, or to other agents such as bacterial lipopolysaccharide (LPS) (7). Inclusion of stem cell factor (c-kit ligand) increases cell yields and permits discrete colonies of DC to be grown in semi-solid culture systems (8). Nevertheless the identification of bona fide DC progenitors remains difficult: DC may share a committed stem cell with monocytes and neutrophils (9); or with T cells, B cells and NK cells (10); or indeed they may differentiate from monocytes. However, it is possible to generate mouse DC from presumptive liver progenitors cultured in the presence of GM-CSF, further maturation being promoted by the presence of type-1 collagen in vitro (11); these progenitors may be capable of seeding secondary lymphoid tissues, and possibly some non-lymphoid tissues, following liver allografting in vivo (12). What stimuli recruit DC progenitors into the tissues? Regarding epithelia, there is evidence that intradermal administration of GM-CSF leads to an increase in numbers of DC within the dermis of human skin, which may be the precursors to epidermal Langerhans cells (LC, the DC of skin epidermis) (13). In addition, GM-CSF produced by normal and inflamed tissues, and some carcinomas, within

SGS1, a Homologue of the Bloom's and Werner's Syndrome Genes, Is Required for Maintenance of Genome Stability in Saccharomyces cerevisiae

Abstract: The Saccharomyces cerevisiae SGS1 gene is homologous to Escherichia coli RecQ and the human BLM and WRN proteins that are defective in the cancer-prone disorder Bloom9s syndrome and the premature aging disorder Werner9s syndrome, respectively. While recQ mutants are deficient in conjugational recombination and DNA repair, Bloom9s syndrome cell lines show hyperrecombination. Bloom9s and Werner9s syndrome cell lines both exhibit chromosomal instability. sgsl Δ strains show mitotic hyperrecombination, as do Bloom9s cells. This was manifested as an increase in the frequency of interchromosomal homologous recombination, intrachromosomal excision recombination, and ectopic recombination. Hyperrecombination was partially independent of both RAD52 and RAD1 . Meiotic recombination was not increased in sgs1 Δ mutants, although meiosis I chromosome missegregation has been shown to be elevated. sgs1 Δ suppresses the slow growth of a top3 Δ strain lacking topoisomerase 111. Although there was an increase in subtelomeric Y9 instability in sgs1 Δ strains due to hyperrecombination, no evidence was found for an increase in the instability of terminal telomeric sequences in a top3 Δ or a sgs1 Δ strain. This contrasts with the telomere maintenance defects of Werner9s patients. We conclude that the SGS1 gene product is involved in the maintenance of genome stability in S. cermisiae .

Locus Control Region Function and Heterochromatin-Induced Position Effect Variegation

Abstract: Human CD2 locus control region (LCR) sequences are shown here to be essential for establishing an open chromatin configuration. Transgenic mice carrying an hCD2 mini-gene attached only to the 3' CD2 transcriptional enhancer exhibited variegated expression when the transgene integrated in the centromere. In contrast, mice carrying a transgene with additional 3' sequences showed no variegation even when the latter integrated in centromeric positions. This result suggests that LCRs operate by ensuring an open chromatin configuration and that a short region, with no enhancer activity, functions in the establishment, maintenance, or both of an open chromatin domain.

Exclusive paternal origin of new mutations in Apert syndrome

Abstract: Apert syndrome results from one or other of two specific nucleotide substitutions, both C→G transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene The frequency of new mutations, estimated as 1 per 65,000 live births, implies germline transversion rates at these two positions are currently the highest known in the human genome Using a novel application of the amplification refractory mutation system (ARMS), we have determined the parental origin of the new mutation in 57 Apert families: in every case, the mutation arose from the father This identifies the biological basis of the paternal age effect for new mutations previously suggested for this disorder

The mismatch repair system contributes to meiotic sterility in an interspecific yeast hybrid.

Abstract: The mismatch repair system is the major barrier to genetic recombination during interspecific sexual conjugation in prokaryotes. The existence of this anti-recombination activity has implications for theories of evolution and the isolation of species. To determine if this phenomenon occurs in eukaryotes, the effect of a deficiency of mismatch repair on the meiotic sterility of an interspecific hybrid of Saccharomyces cerevisiae and the closely related species Saccharomyces paradoxus was examined. The results demonstrate that the rare viable spores from these hybrids have high frequencies of aneuploidy and low frequencies of genetic exchange. Hybrids lacking mismatch repair genes PMS1 or MSH2 display increased meiotic recombination, decreased chromosome non-disjunction and improved spore viability. These observations are consistent with the proposal that the mismatch repair system is an element of the genetic barrier between eukaryotic species. We suggest that an anti-recombination activity during meiosis contributes towards the establishment of post-zygotic species barriers.

DNA repeats identify novel virulence genes in Haemophilus influenzae

Abstract: The whole genome sequence (1.83 Mbp) of Haemophilus influenzae strain Rd was searched to identify tandem oligonucleotide repeat sequences. Loss or gain of one or more nucleotide repeats through a recombination-independent slippage mechanism is known to mediate phase variation of surface molecules of pathogenic bacteria, including H. influenzae. This facilitates evasion of host defenses and adaptation to the varying microenvironments of the host. We reasoned that iterative nucleotides could identify novel genes relevant to microbe-host interactions. Our search of the Rd genome sequence identified 9 novel loci with multiple (range 6-36, mean 22) tandem tetranucleotide repeats. All were found to be located within putative open reading frames and included homologues of hemoglobin-binding proteins of Neisseria, a glycosyltransferase (IgtC gene product) of Neisseria, and an adhesin of Yersinia. These tetranucleotide repeat sequences were also shown to be present in two other epidemiologically different H. influenzae type b strains, although the number and distribution of repeats was different. Further characterization of the IgtC gene showed that it was involved in phenotypic switching of a lipopolysaccharide epitope and that this variable expression was associated with changes in the number of tetranucleotide repeats. Mutation of IgtC resulted in attenuated virulence of H. influenzae in an infant rat model of invasive infection. These data indicate the rapidity, economy, and completeness with which whole genome sequences can be used to investigate the biology of pathogenic bacteria.

A complete set of human telomeric probes and their clinical application

Abstract: Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats1–3. Unique sequence DNA for each telomere is located 100–300 kilobases (kb) from the end of most chromosomes. A high concentration of genes4 and a number of candidate genes for recognizable syndromes5–8 are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis9,10. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100–300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2–3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.

Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications.

Abstract: Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.

Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic neisseriae.

Abstract: Opa protein-expressing pathogenic neisseriae interact with CD66a-transfected COS (African green monkey kidney) and CHO (Chinese hamster ovary) cells. CD66a (BGP) is a member of carcinoembryonic antigen (CEA, CD66) family. The interactions occur at the N-terminal domain of CD66a, a region that is highly conserved between members of the CEA subgroup of the CD66 family. In this study, we have investigated the roles of CD66 expressed on human epithelial cells and polymorphonuclear phagocytes (PMNs) in adhesion mediated via Opa proteins. Using human colonic (HT29) and lung (A549) epithelial cell lines known to express CD66 molecules, we show that these receptors are used by meningococci. A monoclonal antibody, YTH71.3, against the N-terminal domain of CD66, but not 3B10 directed against domains, A1/ B1, inhibited meningococcal adhesion to host cells. When acapsulate bacteria expressing Opa proteins were used, large numbers of bacteria adhered to HT29 and A549 cells. In addition, both CD66a-transfected CHO cells and human epithelial cells were invaded by Opa-expressing meningococci, suggesting that epithelial cell invasion may occur via Opa-CD66 interactions. In previous studies we have shown that serogroup A strain C751 expresses three Opa proteins, all of which mediate non-opsonic interactions with neutrophils. We have examined the mechanisms of these interactions using antibodies and soluble chimeric receptors. The results indicate that the nature of their interactions with purified CD66a molecules and with CD66 on neutrophils is alike and that these interactions occur at the N-terminal domain of CD66. Thus, the Opa family of neisserial ligands may interact with several members of the CD66 family via their largely conserved N-terminal domains.

The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitidis and Neisseria gonorrhoeae.

Abstract: Using COS (African green monkey kidney) cells transfected with cDNAs encoding human cell surface molecules, we have identified human cellular receptors for meningococcal virulence-associated Opa proteins, which are expressed by the majority of disease and carrier isolates. These receptors belong to the immunoglobulin superfamily of adhesion molecules and are expressed on epithelial, endothelial and phagocytic cells. Using soluble chimeric receptor molecules, we have demonstrated that meningococcal Opa proteins bind to the N-terminal domain of biliary glycoproteins (classified as BGP or CD66a) that belong to the CEA (CD66) family. Moreover, the Opa proteins of the related pathogen Neisseria gonorrhoeae, responsible for urogenital infections, also interact with this receptor, making CD66a a common target for pathogenic neisseriae. Over 95% of Opa-expressing clinical and mucosal isolates of meningococci and gonococci were shown to bind to the CD66 N-domain, demonstrating the presence of a conserved receptor-binding function in the majority of neisserial Opa proteins.

ATRX Encodes a Novel Member of the SNF2 Family of Proteins: Mutations Point to a Common Mechanism Underlying the ATR-X Syndrome

Abstract: It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.

Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney

Abstract: Polycystic kidney disease 1 (PKD1) is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease. We have studied PKD1 mRNA, with an RNase protection assay, and found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein, polycystin, was assessed in kidney using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining is restricted to epithelial cells. Expression in the developing nephron is most prominent in mature tubules, with lesser staining in Bowman's capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal was observed in comma- and S-shaped bodies as well as the distal branches of the ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no staining. In later fetal (>20 weeks) and adult kidney, strong staining persists in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. These results suggest that polycystin's major role is in the maintenance of renal epithelial differentiation and organization from early fetal life. Interestingly, polycystin expression, monitored at the mRNA level and by immunohistochemistry, appears higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein.

Novel, Cross-Restricted, Conserved, and Immunodominant Cytotoxic T Lymphocyte Epitopes in Slow Progressors in HIV Type 1 Infection

Abstract: HIV-specific cytotoxic T lymphocytes (CTLs) play an important role in the immune response to HIV infection. Long-term nonprogressors (LTNPs) or slow progressors (SPs) in HIV infection may make qualitatively different CTL responses compared to those generated by seropositive individuals who progress to disease at a faster rate. The class I molecule HLA-B*57 has been identified as one restriction element overrepresented in SP groups studied, and, together with the closely related molecule HLA-B*58, occurs commonly in ethnic groups where HTV is most prevalent. In this study, we have identified five new HLA-B*57-restricted CTL epitopes recognized by SP donors, one of which is also HLA-B*5801 restricted. These HLA-B*57-restricted responses represent the dominant HIV-specific CTL response in each of the SP donors tested. These and other such epitopes may be an important component in future vaccine design.

HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom

Abstract: OBJECTIVE: To investigate the HLA class I associations of ankylosing spondylitis (AS) in the white population, with particular reference to HLA-B27 subtypes. METHODS: HLA-B27 and -B60 typing was performed in 284 white patients with AS. Allele frequencies of HLA-B27 and HLA-B60 from 5926 white bone marrow donors were used for comparison. HLA-B27 subtyping was performed by single strand conformation polymorphism (SSCP) in all HLA-B27 positive AS patients, and 154 HLA-B27 positive ethnically matched blood donors. RESULTS: The strong association of HLA-B27 and AS was confirmed (odds ratio (OR) 171, 95% confidence interval (CI) 135 to 218; p < 10(-99)). The association of HLA-B60 with AS was confirmed in HLA-B27 positive cases (OR 3.6, 95% CI 2.1 to 6.3; p < 5 x 10(-5)), and a similar association was demonstrated in HLA-B27 negative AS (OR 3.5, 95% CI 1.1 to 11.4; p < 0.05). No significant difference was observed in the frequencies of HLA-B27 allelic subtypes in patients and controls (HLA-B*2702, three of 172 patients v five of 154 controls; HLA-B*2705, 169 of 172 patients v 147 of 154 controls; HLA-B*2708, none of 172 patients v two of 154 controls), and no novel HLA-B27 alleles were detected. CONCLUSION: HLA-B27 and -B60 are associated with susceptibility to AS, but differences in HLA-B27 subtype do not affect susceptibility to AS in this white population.

Thalassemia — a global public health problem

Abstract: The thalassemias and related genetic diseases pose public health problems for many countries in the next millennium. Will it be possible to apply research results to their control and management on the scale required?

Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy.

Abstract: The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study.

The epidemiology of malaria in a Karen population on the western border of Thailand

Abstract: From November 1991 to November 1992 a prospective, descriptive study of malaria epidemiology was conducted in a Karen population on the western border of Thailand. Two study groups were selected at random and more than 80% of the subjects were followed for one year. In Group 1, comprising 249 schoolchildren (aged 4–15 years), daily surveillance for illness was combined with fortnightly malaria surveys. These children experienced 1·5 parasitaemic infections per child-year (95% confidence interval [CI] 1·3–1·7), of which 68% (193285) were symptomatic ( Plasmodium falciparum 84%, P. vivax 57%). The estimated pyrogenic densities were 1460/μL for P. falciparum and 181/μL for P. vivax . In Group 2, comprising subjects of all age from 428 households, malaria was diagnosed during two-monthly surveys, at weekly home visits, and otherwise by passive case detection. Malaria and splenomegaly prevalence rates were low in all age groups (spleen index 2–9%; P. falciparum prevalence rate 1–4%; P. vivax 1–6%). Group 2 subjects had 1·0 infections per person-year (95% CI 0·9–1·1), most of which were symptomatic (312357; 87%). Malaria infections clustered in households. Overall, P. vivax caused 53% and P. falciparum 37% of the infections (10% were mixed), but whereas P. vivax was most common in young children, with a decline in incidence with increasing age, P. falciparum incidence rates rose with age to a peak incidence between 20 and 29 years, although the risk of developing a severe malaria decreased with increasing age. There was no death from malaria during the study. P. falciparum infections were more common in males, subjects with a history of malaria before the study, and in those who had travelled outside their village. These findings suggest a higher transmission rate for P. vivax than P. falciparum , although adults still suffered symptomatic malaria due to both species. The 2 malaria parasites found in this area contribute approximately 50% of infections each, but their clinical epidemiology is very different.